Will Alcoholic Mice Teach Scientists About Human Behavior?

By GINA KOLATA

Published: December 26, 1995

THE old question about mice and humans was whether a gene that gave mice cancer would cause the disease in people. Now the question is whether genes that make mice drink alcohol until they fall over dead will also lead to alcoholism in humans.

Despite the explosive implications of the research, a number of scientists are now using mice as models for the genetic roots of human behavior. They are actively searching for inbred strains of mice with behaviors like a love of alcohol or an instinctual violent streak. They are isolating collections of mouse genes that cause those behaviors. Then, they say, they will look for similar genes in humans. Finally, they will ask whether people who have those genes also have predispositions to the behavior being studied.

It is a strategy that is also being employed to look for collections of genes that predispose mice and humans to diseases like cancer, diabetes, heart disease and high blood pressure. For example, scientists first find high blood pressure genes in mice, then similar genes in humans. Finally they test people with and without high blood pressure to see whether the putative high blood pressure genes are more common in people whose blood pressure is elevated.

The difference, of course, is that investigating the possible genetic roots of human behavior is highly controversial. In fact, it is so controversial that some critics of the research say that perhaps it should not be done at all.

The behavioral genetics studies are only beginning. Dr. Solomon Snyder, a neurobiologist at the Johns Hopkins University School of Medicine, has genetically engineered mice to produce extremely aggressive strains, but not for this sort of research. He said: "Normally, people have been dubious that you can transfer from mice to man when it comes to complex behavior. But the more you look at things, the more you see that it's not so farfetched."

Dr. Lee Silver, a molecular geneticist at Princeton University, said: "Five years ago, people would say that it doesn't matter if there are genes for intelligence because even if there are, we'll never find them." But now, he said, with the mouse work, "we're going to find them."

"The mouse stuff is really banging along," said Dr. Robert Plomen, a professor at the Institute of Psychiatry in London. Dr. Plomen recently was awarded $2.5 million by the British Government to do work on addiction and mental disorders in mice.

The behavioral geneticists cite several reasons why the time is right for their studies. First, they say, it has become clear that mice have essentially the same genes as humans, but rearranged.

"Every gene in humans seems to have a homologue in mice," Dr. Silver said. "It doesn't always do the same thing, but if you look at the size of the mouse genome, it's the same size as the human genome. And if you look at the chromosomes themselves, you can make the human genome by breaking the mouse genome into about 200 pieces and then rearranging them."

To make the connection between mouse and human even simpler, the Federal Human Genome Project is paying for an explosion of research that is mapping both human and mouse genes. That makes it increasingly easy to find a gene on a mouse chromosome and then almost immediately spot a gene just like it on a human chromosome.

Mice have another advantage for behavioral research. Researchers have developed hundreds of inbred strains, with each strain consisting of genetically identical mice. The strains were not developed for behavioral studies, but mice of different strains turn out to differ in behavior. And each mouse of a particular strain behaves exactly the same way.

"Let's take alcohol," Dr. Silver said. "I can look at any strain and tell you exactly how much this animal will drink -- some drink in moderation, some drink in excess, and some don't drink at all."

And alcoholism is just the beginning. More than two dozen groups of researchers are plunging into this new field. Investigators like Dr. Wade H. Berrettini at Thomas Jefferson University in Philadelphia are looking for genes that predispose to heroin addiction. Dr. Silver, already studying alcohol addiction, is also looking at nicotine addiction and aggression with mouse models. Dr. John Crabbe of the Oregon Health Sciences University in Portland is studying alcoholism and drug addiction. Others are investigating mental illnesses. "Even for something like schizophrenia, it's not impossible to find mouse models," Dr. Plomen said.

"The neat thing is that you don't have to argue, is the mouse model reasonable at the behavioral level," Dr. Plomen said. The mouse research is a way to fish for genes that seem to have a certain effect. Having found such genes, researchers can then look for them in human beings and try to find out if they are associated with the behaviors in question.

"All we're doing is nominating candidate genetic regions, and then we'll test them in humans," Dr. Plomen said. If the genes are not affecting behavior in people that will soon come clear. For example, if researchers find mouse genes for something that looks like aggression, they may then find no correlation between those genes and aggressive behavior in people.

The key to using mice to find such genes, Dr. Silver said, is to find a simple way to measure whether a mouse has a trait of interest, called an assay. The assay must be simple because the researchers must test thousands of mice to get enough data for analysis.

For alcohol preference, the standard test is to give mice two bottles, one containing alcohol and one containing water, and to ask how much of each liquid the animals drink.

Aggression is more difficult to study. "The problem is in defining aggression," Dr. Silver said. "When we use the word, we can mean 100 different things." But, he said, "we set up a very specific assay and, with our assay, the behavior is inherited."

He puts a male mouse in a cage and then puts another male on top of the cage. "The mouse on top is passive. The question is, will the mouse in the cage jump up and attack the mouse on top?" Dr. Silver said. "This is an all-or-none assay," he said. "We find that either they jump in three minutes or they aren't going to jump."

Dr. Silver even has an assay for mouse intelligence. He puts mice in a pool of water with a platform a short distance away. He observes if the mice can figure out that they can swim to the platform and stand on it to avoid drowning.

Of course, assays can be misleading, as Dr. Berrettini discovered when he was looking for mice that prefer morphine. He gave mice a choice of drinks. One bottle contained morphine, water and a bit of saccharine to mask the bitter taste of the drug. The other contained quinine -- another bitter substance -- water and saccharine to cover quinine's taste. "I tasted those solutions and they were both sweet to me, but who knows what a mouse can taste?" Dr. Berrettini said.

He found that two genes seemed to determine whether the animals liked or did not like the morphine -- a much smaller number of genes than he expected. But, he said, "the second gene turned out to be a little silly." It was a gene that made mice hate quinine -- so much so that to avoid it they would actually drink morphine. When Dr. Berrettini repeated his experiment without quinine in the control bottle, he found that just a single gene that apparently makes mice love morphine was determining behavior.

None of the mice researchers are suggesting that humans are helpless before their genes. "I disagree with people who say that genes are everything in humans," Dr. Silver said. "Those people don't understand a couple of notions. Even if you're predisposed, that just means that your probability of having the behavior is greater. All these genes do is increase predispositions. And human behavior, if anything, has to be under an enormous number of influences. I'm as angry with those who say it's all genetic as I am with those who say it's not genetic at all," Dr. Silver said.

Some critics say, however, that the behavioral genetic studies are ethically and scientifically suspect. Dr. Angela Creager, a historian of molecular biology at Princeton University, said she was deeply concerned about the implications of some of the work, like studies of genes controlling aggression and intelligence.

Dr. Creager, who is a friend of Dr. Silver of Princeton, said: "I really understand how he as a scientist is led by his curiosity and the power of new techniques to follow up on these things. But there are times when I say, What is the good of knowledge that we think can only be abused?" And she added, "to the degree that the taxpaying public continues to fund this research, there are legitimate questions about how we feel about it."

Another friend of Dr. Silver, Dr. Vincanne Adams, a medical anthropologist at Princeton, said she was concerned that if the behavioral genes are found, people who have them will become pariahs. She said she fears that the investigators distance themselves from the ethical implications of their work because they are studying mice. But, she said, "we're making the mice stand in for humans." That, she said, "is what authorizes the funding."

"I question the ethics" of the mouse research, said Dr. Evan S. Balaban, a senior fellow in experimental neurobiology at the Neurosciences Institute in San Diego. Dr. Balaban added that the mouse research sounds hopelessly naive because it ignores complex interactions that occur among thousands of genes. Changes in one set of genes, he said, may affect behavior in only the most indirect ways, but may be presented by the researchers as being the genes for aggression, for example.

Dr. Crabbe, in Oregon, who does research in addiction with mice, said he recognizes that the social implications of his work cannot be ignored. "I think that this is something that everyone in the game of genetics of behavior is going to have to pay a lot more attention to," he said. "We're not near having something that can be abused," he said. "But I think that within a few years, we'll be there.

"You can paint the rosy scenario or you can paint the paranoid scenario. I don't know which is more likely."